Strategies of Anti-Inflammatory Therapy:
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Target a single mediator – antihistamines and leukotriene modifiers
i. Antihistamines: H1 – inverse agonists / comp antagonists
1. H1 – Old: Diphenhydramine & Chlorpheniramine
2. H1 – New: Cetrizine / Loratadine / Fexofenadine
ii. Leukotriene antagonists to CysLTR1 :
1. Zafirlukast
2. Montelukast – better b/c no meal restrictions
Target multiple mediators – anti-inflammatory steroids, NSAIDs (shot-gun approach)
i. COX pathway
1. Aspirin – irreversibly inhibits COX
2. tNSAIDs – non-selective COX inhibitor
a. Ibuprofen – less GI SE than Aspirin
b. Naproxen
c. Diflunisal
d. Ketoprofen
e. Indomethacin – MOST POTENT
f. Sulindac
g. Piroxicam  bad GI bleed
3. Selective COX2 inhibitors – Celecoxib
4. Acetominophen – Tylenol – FEVER AND PAIN!
Stop mediator production – synthesis inhibitors
i. LTs – 5-LO inhibitor: Zileuton
Stop mediator release
Stop mediator action – antagonists or inverse agonists
i. Kinin receptor antagonist: Icatibant – for C1 inhibitor def
Cortisol is an anti-inflammatory!
Synthetic steroids: bethamethasone, dexamethasone, methylprednisone, predinisone
Calcineurin inibs – post organ transplant – both block DEPHOSPHORYLATION needed for cytokine GENE
EXPRESSION & T cell activation
o Cyclosporine to cyclphilin
o Tacroliums to FKBP
Antiproliverative/antimetabolic drugs
o Sirolimus: INHIBITS ENZYME NEEDED FOR CELL PROLIFERATION of T cell. – cell cycle
o M. mofetil: INHIBITS IMPDH needed for de novo guanine synthesis
o Other anticancer drugs: azatioprine, methotrexate, cyclophosphamide
Abs:
o Muromonab-CD3 – blocks CD3 on TCR
o Daclizumab or Basiliximab bind to IL-2 receptor
Anti-inflammatory & Immunosuppressive Drugs (Regal)
INFLAMMATION overview:
(1)
Inflammation is a process: Sublethal injury  Mediators  Inflammation (redness, swelling, heat, pain)
 Injury d/t: heat, mechanical, chemical, bacteria, virus, Ab-Ag reactions
 Mediators: endogenous substances (autacoids/local hormones) that are stored or rapidly
synthesized, intended to act only at the site of injury. Lots of redundancy!
Fever
Pain (either causes
pain or reduces pain
threshold)
PGEs
(2)
(3)
Redness & heat
(vasodilation)
Swelling (
permeability)
PGE₂
Histamine
PGE₂
Histamine
Peptidoleukotrienes (LTC₄,
LTD₄, LTE₄)
PGI₂ - prostacyclin
PGI₂ - prostacyclin
Kinins
Kinins
Kinins
Chemotaxis
Peptidoleukotrienes
(eosinohpils)
LTB₄
(neutrophils)
Airway
constriction
Hypotension
Histamine
Peptidoleukotrienes
(LTC₄, LTD₄, LTE₄)
PGD₂
Histamine
Kinins
Kinins
Acute inflammation review:
 Changes in blood vessel caliber & flow : arteriolar dilation, increased blood flow, slowing of flow to
stasis. This causes redness & heat.
 Increased vascular permeability : post capillary venules leak large molecules, contraction of
endothelium w/ spaces in bxt. This causes swelling which can lead to pain.
 Leukocytic infiltration : post capillary venules, pavementing of leukocytes, mvmt into
extravascular space, chemotaxis
 Mediators that will cause all this to occur: Histamine, Prostaglandins, Leukotrienes, Platelet
Activating Factor (PAF), kinins, products of complement system activation, cytokines, chemokines,
interleukins, adhesion molecules.
i. Mediators in any given situation will differ depending on: nature and extent of injury,
location of injury, type of Ag-Ab rxn
 Airway constriction (bronchoconstriction) is relevant in asthma (immune mediated lung disease)
 Hypotension is relevant in shock (systemic release of inflammatory mediators). Can be d/t
widespread vasodilation, increased capillary permeability & fluid loss from circulation!
Strategies of Anti-Inflammatory Therapy:
 Target a single mediator – antihistamines and leukotriene modifiers
 Target multiple mediators – anti-inflammatory steroids, NSAIDs (shot-gun approach)
 Stop mediator production – synthesis inhibitors
 Stop mediator release
 Stop mediator action – antagonists or inverse agonists
IMMUNOSUPPRESSION:
(1)
(2)
(3)
Immunosuppressive drugs are used to dampen the immune system in organ transplantation,
autoimmune disease & hypersensitivity. Works best on primary immune response. Will work better if
therapy starts before exposure to immunogen. Want to do this so you don’t get immune mediated tissue
damage which thereby means you don’t have an inflammatory response related to the tissue damage.
Limitations include:  risk of all infections and lymphomas & related malignancies
Major classes of immunosuppressive drugs:
 Glucocoriticoids = Anti-inflammatory steroids. Made by adrenal cortex. Cortisol turns off
immune system as a negative feedback inhibitor = natural anti-inflammatory system.
i. Corticosteroids (21C) are released in response to stimulation by ACTH.
1. Mineralocorticoids (electrolyte balance)
2. Glucocotriocoids (carbohydrate metabolism)
Activity:
Prototype
Compound
Sodium Retention
(can the steroid  Na
excretion by kidney?)
Mineralocorticoids
Glucocorticoids
Aldosterone
Cortisol
+
-
Liver Glycogen
Deposition (can the
steroid cause hepatic
deposition of
glycogen?)
+
Anti-Inflammatory
+
ii. Androgens (19C)
1. NOT body building
iii. Why do we use anti-inflammatory steroid drugs?? When immune system is too active,
the addition of exogenous glucocorticoids can turn it off (endogenous ones are doing
their job). Want to minimize drug action on the mineralocorticoid receptor.
1. Synthetic steroids: Betamethasone, Dexamethasone, Methylprednisone,
Prednisone
2. Oral, parenteral & topical administration. Some systemic absorption always
occurs. Metabolized by liver & excreted by kidney.
3. Inhaled glucocorticoids are designed for uptake & prolonged tissue binding in
airway.
4. How do steroids work?? Time lag in steroid action. There are a number of
protein products responsible for immunosuppressive effects. Steroid GR complex
interacts w/ TFs which can repress gene expression.
iv. Effects of glucocorticoids on ppl:
1. Effects on cell mvmt
a. Neutrophils – more of them, release from BM , in circulation longer,
blockage of migration to inflammatory sites by  adherence
b. Lymphocytes – lymphopenia, cells not lysed, but move to extravascular
compartments
c. Monocytes & eosinohpils are decreased in peripheral blood
2. Effects on synthesis &/or release of inflammatory mediators
a. Reduced expression of COX2
b. Inhibits release of arachidonic acid from PLs =  PG & LT production
c. Inhibits degranulation of mast cells and basophils
d. Inhibits synthesis & release of TNF, IL1, IL2 and IFN
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v. Therapy:
1. W/ systemic admin  SE can be life threatening
2. Cortisol & analogs prevent / suppress R, S, H P…but underlying cause of disease
remains
3. Lowers host resistance to microbial and fungal infection.
vi. Therapeutic principles:
1. Dosing often by trial & error
2. Single dose OK; a few days OK as long as not high dose…prolonged = BAD!
a. also…don’t just take someone off a long dose, need to TAPER
vii. Uses:
1. Arthritis
2. Rheumatic carditis
3. Renal diseases - SLE nephrotic syndrome
4. Collagen diseases - systemic lupus
5. Allergic diseases - not acute anaphylaxis
6. Bronchial asthma - inhalation, systemically
7. Ocular diseases - in bacterial, fungal or viral infection, glucocorticoids can mask
the progression of the disease
8. Skin diseases – eczema
9. Diseases of the intestinal tract - chronic ulcerative colitis
10. Malignancies
11. Diseases of the liver
12. Shock - use is controversial
Calcinerin inhibitors – in immunosuppression after organ transplantation
i. Cyclosporine: binds to cytoplasmic receptor protein called cyclophilin  inhibiting
caclineurin activity. Blocks dephosphorylation events needed for cytokine gene
expression & T cell activation.
1. Met in liver
2. Lots of drug interactions
3. Long term tx for transplantation
4. Renal toxicity – BAD SE
ii. Tacrolimus (FK506): binds to cytoplasmic receptor called FKBP  inhibition of calcineurin.
Blocks same stuff
1. 100 times more potent than cyclosporine
2. Toxicity similar nephrotoxicity
Antiproliferative/antimetabolic drugs – prevent clonal expansion of both B & T cells
i. Sirolimus (rapamycin): binds to FKBP to inhibit enzyme needed for cell
cycle proliferation – blocks G1  S in IL driven T cell proliferation.
1. Toxicity: WORSE than Aspirin!
ii. Mycophenolate mofetil: a metabolite is an inhibitor of inosine
monophosphate dehydrogenase (IMPDH), an imp enzyme in the de
novo pathway of guanine nt syn. B & T cells are highly dependent on
de novo synthesis of purines for cell proliferation, while other cells can
use salvage pathways.
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iii. Other anticancer drugs like azathioprine, methotrexate & cyclophosphamide
1. Immune cells prolif in response to a specific Ag, Ca cells just go nuts. Low doses
block immunoproliferation & high dose will kill cancer cells. DOSING
Antibodies
i. Eliminate lymphocytes
1. Anti-thymocyte globulin: purified Igs. Will bind to thymocytes in circulation 
lymphopenia & impaired T cell immune response
a. Toxicity: Ig being seen as foreign  serum sickness & nephritis
ii. Affect T cell function
1. Muromonab-CD3 (for kidney, liver and heart transplants)
a. Ab binds to CD3, TCR can’t work. Can cause cytokine release syndrome:
i. Flu-like sx  life-threatening shock. Crosslinking = cytokine
release
2. Daclizumab or Basiliximab (organ transplantation)
a. Mouse Ab to IL-2 receptor
b. Bind to IL-2 receptor on activated but not resting T cells and block IL-2
mediated T cell activation
c. Anaphylaxis can occur. No cytokine release syndrome
Site of Action of Selected Immunosuppressive Agents on T Cell Activation
DRUG
SITE OF ACTION
Glucocorticoids
Glucocorticoid response elements in DNA (regulate gene transcription)
Cyclosporine
Calcineurin (inhibits phosphatase activity)
Tacrolimus
Calcineurin (inhibits phosphatase activity)
Sirolimus
Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity)
Mycophenolate mofetil
Inosine monophosphate dehydrogenase (inhibits activity)
Muromonab-CD3 (Ab)
T-cell receptor complex (blocks antigen recognition)
Daclizumab, Basiliximab (Ab)
IL-2 receptor (block IL-2-mediated T-cell activation)